The present invention is concerned with novel compounds of formula (I) having HIV replication inhibiting properties. The invention further relates to methods for preparing such novel compounds, pharmaceutical compositions comprising said novel compounds as well as the use as a medicine of said compounds.
Compounds structurally related to the present novel compounds are disclosed in the prior art. DE-2,121,694, published on Nov. 25, 1971, discloses a number of s-triazines useful as anti-inflammatory, tranquillising, antiviral, antispasmodic, hypo-glycaemic, diuretic, and vasodilating agents, and for modifying adreno-cortico hormone secretion. DE-2,226,474, published on Feb. 22, 1973, discloses diamino- 1,3,5-triazine derivatives with hormone secretion-increasing activity, and anti-inflammatory effect. Substituted triazines having diuretic activity were published in Guioca, Ann. Pharm. Fr., 31:283 -292 (1973). A number of 2,4-diamino-triazines were prepared in Kelarev V.I. et al., Khim. GeterotsikL. Soedin., 1392-1397 (1987) and Kelarev V.I. et al., Khim. Geterotsikl. Soedin., 1395-1399 (1992). The preparation of 2-amino-4-benzyl-6-o-toluidino-s-triazine was described in Yuki Y. et al., Kobunshi Kagaku, 26: 141-147 (1969). The use of aralkylguanamines, in particular 2-amino-4-anilino-6-benzyl-s-triazine, for the manufacture of resins is disclosed in U.S. Pat. No. 2,817,614, granted Dec. 24, 1957.
Unexpectedly, it has now been found that the compounds of formula (I) effectively inhibit the replication of the Human Immunodeficiency Virus (HIV) and consequently may be useful for the treatment of individuals infected by HIV.
The present invention concerns the use of compounds of formula 
the pharmaceutically acceptable acid addition salts and the stereochemically isomeric forms thereof, wherein
R1 and R2 are each independently selected from hydrogen; hydroxy; amino; C1-6alkyl; C1-6alkyloxy; C1-6alkylcarbonyl; C1-6alkyloxycarbonyl; Ar1; mono- or di(C1-6alkyl)amino; mono- or di(C1-6alkyl)aminocarbonyl; dihydro-2(3H)-furanone; C1-6alkyl substituted with one or two substituents each independently selected from amino, imino, aminocarbonyl, aminocarbonylamino, hydroxy, hydroxyC1-6alkyloxy, carboxyl, mono- or di(C1-6alkyl)amino, C1-6alkyloxycarbonyl and thienyl; or
R1 and R2 taken together may form pyrrolidinyl, piperidinyl, morpholinyl, azido or mono- or di(C1-6alkyl)aminoC1-4alkylidene;
R3 is hydrogen, Ar1, C1-6alkylcarbonyl, C1-6alkyl, C1-6alkyloxycarbonyl, C1-6alkyl substituted with C1-6alkyloxycarbonyl; and
R4, R5, R6, R7 and R8 are each independently selected from hydrogen, hydroxy, halo, C1-6alkyl, C1-6alkyloxy, cyano, aminocarbonyl, nitro, amino, trihalomethyl or trihalomethyloxy;
L is C1-10alkyl; C3-10alkenyl; C3-10alkynyl; C3-7cycloalkyl; or
L is C1-10alkyl substituted with one or two substituents independently selected from C3-7cycloalkyl; indolyl or indolyl substituted with one, two, three or four substituents each independently selected from halo, C1-6alkyl, C1-6alkyloxy, cyano, aminocarbonyl, nitro, amino, trihalomethyl, trihalomethyloxy, C1-6alkylcarbonyl; phenyl or phenyl substituted with one, two, three, four or five substituents each independently selected from halo, hydroxy, C1-6alkyl, C1-6alkyloxy, cyano, aminocarbonyl, nitro, amino, trihalomethyl, trihalomethyloxy, C1-6alkylcarbonyl; and,
Ar1 is phenyl, or phenyl substituted with one, two or three substituents each independently selected from halo, C1-6alkyl, C1-6alkyloxy, cyano, nitro or trifluoromethyl; for the manufacture of a medicine for the treatment of subjects suffering from HIV (Human Immunodeficiency Virus) infection.
This invention also concerns novel compounds of formula 
the pharmaceutically acceptable acid addition salts and the stereochemically isomeric forms thereof, wherein the substituents are as defined under formula (I); with the proviso that compounds (a) to (o) are not included.
The proviso is intended to exclude compounds (a) to (f) disclosed in DE-2,121,694 and DE-2,226,474; compound (g) disclosed in DE-2,226,474; compounds (h) to (k) disclosed in Guioca, Ann. Pharm. Fr., 31:283-292 (1973); compounds (l) disclosed in Kelarev V.I. et al., Khim. Geterotsikl. Soedin., 1392-1397 (1987); compound (m) disclosed in Kelarev V.I. et al., Khim. Geterotsikl. Soedin., 1395-1399 (1992); compound (n) disclosed in Yuki Y. et al., Kobunshi Kagaku, 26: 141-147 (1969); and compound (o) disclosed in U.S. Pat. No. 2,817,614.
As used in the foregoing definitions and hereinafter halo defines fluoro, chloro, bromo and iodo; C1-2alkyl includes methyl and ethyl; C1-3alkyl defines straight and branched chained saturated hydrocarbon radicals having from 1 to 3 carbon atoms such as, for example, methyl, ethyl, propyl and the like; C1-4alkyl encompasses the straight and branched chained saturated hydrocarbon radicals as defined in C1-3alkyl as well as the higher homologues thereof containing 4 carbon atoms such as, for example, butyl and the like; C1-6alkyl encompasses the straight and branched chained saturated hydro-carbon radicals as defined in C1-4alkyl as well as the higher homologues thereof containing 5 or 6 carbon atoms such as, for example pentyl or hexyl; C3-6alkyl defines straight and branched chained saturated hydrocarbon radicals having from 3 to 6 carbon atoms such as, for example, propyl, butyl, pentyl, hexyl and the like; C2-6alkyl encompasses the straight and branched chained saturated hydrocarbon radicals as defined in C3-6alkyl as well as ethyl; C1-10alkyl encompasses the straight and branched chained saturated hydrocarbon radicals as defined in C1-6alkyl as well as the higher homologues thereof containing 7 to 10 carbon atoms such as, for example heptyl, octyl, nonyl or decyl; C1-4alkylidene defines bivalent straight and branched chained hydro-carbons having from 1 to 4 carbon atoms such as, for example, methylene, ethylidene, propylidene, butylidene and the like; C3-7cycloalkyl is generic to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl; C3-10alkenyl defines straight and branch chained hydrocarbon radicals containing one double bond and having from 3 to 10 carbon atoms such as, for example, 2-propenyl, 2-butenyl, 2-pentenyl, 3-pentenyl, 3-methyl-2-butenyl, 3-hexenyl, 3-heptenyl, 2-octenyl, 2-nonenyl, 2-decenyl and the like, whereby the carbon atom attached to the triazine ring is preferably an aliphatic carbon atom; C3-10loalkynyl defines straight and branch chained hydrocarbon radicals containing one triple bond and having from 3 to 10 carbon atoms such as, for example, 2-propynyl, 2-butynyl, 2-pentynyl, 3-pentynyl, 3-methyl-2-butynyl, 3-hexynyl, 3-heptynyl, 2-octynyl, 2-nonynyl, 2-decynyl and the like, whereby the carbon atom attached to the triazine ring is preferably an aliphatic carbon atom; C1-6alkanediyl defines bivalent straight and branched chained saturated hydrocarbon radicals having from 1 to 6 carbon atoms, such as, for example, methylene, 1,2-ethanediyl, 1,3-propanediyl, 1,4-butanediyl, 1,5-pentanediyl, 1,6-hexanediyl and the branched isomers thereof.
The pharmaceutically acceptable acid addition salts as mentioned hereinabove are meant to comprise the therapeutically active non-toxic acid addition salt forms which the compounds of formula (I) or (Ixe2x80x2) are able to form. The compounds of formula (I) or (Ixe2x80x2) which have basic properties can be converted in their pharmaceutically acceptable acid addition salts by treating said base form with an appropriate acid. Appropriate acids comprise, for example, inorganic acids such as hydrohalic acids, e.g. hydrochloric or hydrobromic acid; sulfuric; nitric; phosphoric and the like acids; or organic acids such as, for example, acetic, propanoic, hydroxyacetic, lactic, pyruvic, oxalic, malonic, succinic (i.e. butanedioic acid), maleic, fumaric, malic, tartaric, citric, methanesulfonic, ethanesulfonic, benzenesulfonic, p-toluenesulfonic, cyclamic, salicylic, p-aminosalicylic, pamoic and the like acids.
The term addition salts also comprises the hydrates and the solvent addition forms which the compounds of formula (I) or (Ixe2x80x2) are able to form. Examples of such forms are e.g. hydrates, alcoholates and the like.
The term stereochemically isomeric forms of compounds of formula (I) or (Ixe2x80x2), as used hereinbefore, defines all possible compounds made up of the same atoms bonded by the same sequence of bonds but having different three-dimensional structures which are not interchangeable, which the compounds of formula (I) or (Ixe2x80x2) may possess. Unless otherwise mentioned or indicated, the chemical designation of a compound encompasses the mixture of all possible stereochemically isomeric forms which said compound may possess. Said mixture may contain all diastereomers and/or enantiomers of the basic molecular structure of said compound. All stereochemically isomeric forms of the compounds of formula (I) or (Ixe2x80x2) both in pure form or in admixture with each other are intended to be embraced within the scope of the present invention.
Some of the compounds of formula (I) or (Ixe2x80x2) may also exist in their tautomeric forms. Such forms although not explicitly indicated in the above formula are intended to be included within the scope of the present invention.
Whenever used hereinafter, the term xe2x80x9ccompounds of formula (I) or (Ixe2x80x2)xe2x80x9d is meant to include also the pharmaceutically acceptable acid addition salts and all stereoisomeric forms.
A special group of compounds are the compounds of formula (I-P) and include those compounds of formula (I) or (Ixe2x80x2) wherein
R1 and R2 are each independently selected from hydrogen, C1-6alkyl, Ar1 or mono- or di(C1-6alkyl)aminocarbonyl; or
R1 and R2 taken together may form pyrrolidinyl, piperidinyl or morpholinyl;
R3 is hydrogen, C1-6alkyl or Ar1; and
Ar1 is phenyl, or phenyl substituted with 1, 2 or 3 substituents each independently selected from halo, C1-6alkyl, C1-6alkyloxy, cyano, nitro or trifluoromethyl; and
L is a radical of formula 
wherein Alk is C1-6alkanediyl;
Ra, Rb, Rc, Rd, Re, R4, R5, R6, R7 and R8 are each independently select from hydrogen, halo, C1-6alkyl, C1-6alkyloxy, cyano, aminocarbonyl, nitro, amino, trihalomethyl or trihalomethyloxy; or
Ra and Rb taken together may form a bivalent radical of formula
xe2x80x94CHxe2x95x90CHxe2x80x94NR9xe2x80x94xe2x80x83xe2x80x83(a-1),
xe2x80x94NR9xe2x80x94CHxe2x95x90CHxe2x80x94xe2x80x83xe2x80x83(a-2),
wherein R9 is hydrogen or C1-4alkyl.
Another special group of compounds are those compounds of formula (I-P) wherefrom the compounds (a) through (o) are excluded, said compounds being represented by formula (Ixe2x80x2-P).
Interesting compounds are those compounds of formula (Ixe2x80x2) wherein NR1R2 is other than amino.
Other interesting compounds are those compounds of formula (Ixe2x80x2) wherein L is C1-10alkyl; C3-10alkenyl; C3-10alkynyl; C3-7cycloalkyl; or L is C1-10alkyl substituted with one or two substituents independently selected from C3-7cycloalkyl; indolyl or indolyl substituted with one, two, three or four substituents each independently selected from halo, C1-6alkyl, C1-6alkyloxy, cyano, aminocarbonyl, nitro, amino, trihalomethyl, trihalomethyloxy, C1-6alkylcarbonyl; phenyl substituted with one, two, three, four or five substituents each independently selected from halo, C1-3alkyl, C3-6alkyloxy, cyano, aminocarbonyl, nitro, amino, trihalomethyl, trihalomethyloxy, C1-6alkylcarbonyl.
Still other interesting compounds are those compounds of formula (I) wherein one of the following restrictions apply:
i) R4 is hydroxy, halo, C2-6alkyl, C1-6alkyloxy, cyano, aminocarbonyl, amino, trihalomethyl or trihalomethyloxy; or
ii) R5 is hydroxy, halo, C1-3alkyl, C1-6alkyloxy, cyano, aminocarbonyl, nitro, amino, or trihalomethyloxy; or
iii) R6 is C2-6alkyl, C1-6alkyloxy, cyano, aminocarbonyl, nitro, trihalomethyl or trihalomethyloxy; or
iv) R7 is hydroxy, halo, C1-3alkyl, C1-6alkyloxy, cyano, aminocarbonyl, nitro, amino, trihalomethyl or trihalomethyloxy; or
v) R8 is hydroxy, halo, C1-6alkyl, C1-6alkyloxy, cyano, aminocarbonyl, nitro, amino, trihalomethyl or trihalomethyloxy.
Particular compounds are those compounds of formula (I) or (Ixe2x80x2) wherein L is C3-10alkenyl or C1-2alkyl substituted with one or two substituents independently selected from C3-7cycloalkyl; indolyl or indolyl substituted with one, two, three or four substituents each independently selected from halo, C1-6alkyl, C 1-6alkyloxy, cyano, aminocarbonyl, nitro, amino, trihalomethyl, trihalomethyloxy, C1-6alkylcarbonyl; phenyl or phenyl substituted with one, two, three, four or five substituents each independently selected from halo, hydroxy, C1-6alkyl, C1-6alkyloxy, cyano, amino carbonyl, nitro, amino, trihalomethyl, trihalomethyloxy, C1-6alkylcarbonyl; more in particular, wherein L is C5-8alkenyl or C1-2alkyl substituted with one or two substituents independently selected from cyclopropyl; indolyl or indolyl substituted with halo; phenyl or phenyl substituted with one, two, three, four or five substituents each independently selected from halo, hydroxy, C1-6alkyl, C1-6alkyloxy, trihalomethyl, trihalomethyloxy, C1-6alkylcarbonyl.
Also particular compounds are those compounds of formula (I) or (Ixe2x80x2) wherein R4, R7 and R8 are hydrogen and R5 and R6 each independently are hydrogen, cyano, halo or aminocarbonyl; more in particular, wherein R4, R5, R7 and R8 are hydrogen and R6 is cyano.
Other particular compounds are those compounds of formula (I) or (Ixe2x80x2) wherein R1 and R2 are each independently selected from hydrogen; hydroxy; amino; C1-6alkyl; C1-6alkyloxy; C1-6alkylcarbonyl; C1-6alkyloxycarbonyl; Ar1; mono- or di(C1-6alkyl) aminocarbonyl; dihydro-2(3H)-furanone; C1-6alkyl substituted with one or two substituents each independently selected from amino, imino, aminocarbonyl, amino carbonylamino, hydroxy, hydroxyC1-6alkyloxy, carboxyl, mono- or di(C1-6alkyl)amino, C1-6alkyloxycarbonyl and thienyl; or R1 and R2 taken together form azido or mono- or di(C1-6alkyl)aminoC1-4alkylidene; more in particular wherein R1 is hydrogen and R2 is hydrogen; hydroxy; amino; C1-6alkyl; C1-6alkyloxy; C1-6alkylcarbonyl; C1-6alkyloxy carbonyl; Ar1; mono- or di(C1-6alkyl)aminocarbonyl; dihydro-2(3H)-furanone; C1-6alkyl substituted with one or two substituents each independently selected from amino, imino, aminocarbonyl, aminocarbonylamino, hydroxy, hydroxyC1-6alkyloxy, carboxyl, mono- or di(C1-6alkyl)amino, C1-6alkyloxycarbonyl or thienyl.
A preferred group of compounds are those compounds of formula (I) or (Ixe2x80x2) wherein L is 2,6-dichlorophenylmethyl.
Another preferred group of compounds are those compounds of formula (I) or (Ixe2x80x2) wherein R3 is hydrogen, R4, R5, R7 and R8 are hydrogen and R6 is cyano.
Yet another group of preferred compounds are those compounds of formula (I) or (Ixe2x80x2) wherein R1 is hydrogen and R2 is hydrogen or hyroxy.
More preferred are those compounds or formula (I) or (Ixe2x80x2) wherein L is 2,6-dichlorophenylmethyl, R3 is hydrogen, R4, R5, R7 and R8 are hydrogen and R6 is cyano.
Most preferred compounds are 4-[[4-amino-6-[(2,6-dichlorophenyl)methyl]-1,3,5-triazin-2-yl]amino]benzonitrile; 4-[[4-[(2,6-dichlorophenyl)methyl]-6-(hydroxyamino)-1,3,5-triazin-2-yl]amino]benzonitrile and the pharmaceutically acceptable acid addition salts thereof.
In general, compounds of formula (I) can be made according to the methods described in DE-2,121,694, DE-2,226,474 and Guioca, Ann. Pharm. Fr., 31:283-292 (1973).
The compounds of formula (I-a), being compounds of formula (I) wherein R1 and R2 are hydrogen, can be prepared by reacting an intermediate of formula (II) with an intermediate of formula (III) in a reaction-inert solvent such as, e.g. N,N-dimethyl formamide. 
Compounds of formula (I-b), being compounds of formula (I) wherein R3 is hydrogen, can be prepared by reacting an intermediate of formula (IV) with an intermediate of formula (V) in a reaction-inert solvent such as, e.g. N,N-dimethylformamide. 
Compounds of formula (I) wherein L is C1-10alkyl substituted with indolyl or indolyl substituted with one, two, three or four substituents each independently selected from halo, C1-6alkyl, C1-6alkyloxy, cyano, aminocarbonyl, nitro, amino, trihalomethyl, trihalomethyloxy, C1-6alkylcarbonyl, said substituents being represented by (Rxe2x80x2), whereby n is 1 to 4 and said compounds being represented by formula (I-c), may be prepared by deprotecting an intermediate of formula (VI) wherein P is a suitable protecting group such as, for example, a toluenesulfonyloxy group or the like, according to art-known deprotection techniques such as refluxing in a reaction-inert solvent, e.g. water, methanol or a mixture thereof, in the presence of a base, e.g. potassium carbonate or the like. 
Compounds of formula (I) wherein R1 is hydrogen, said compounds being represented by formula (I-d), can be prepared by reacting an intermediate of formula (VII) wherein W1 is a suitable leaving group such as, for example, a halogen, with an amino derivative of formula (VIII) in a reaction inert solvent such as, for example, 1,4-dioxane and the like, in the presence of a suitable base such as, for example, sodiumhydroxide, triethylamine or N,N-diisopropylethylamine or the like. 
In case R2 contains a hydroxy moiety, it may be convenient to perform the above reaction with a protected form of intermediate (VIII) whereby the hydroxy moiety bears a suitable protecting group P being, for instance, a trialkylsilyl group, and subsequently removing the protective group according to art-known methodologies.
Compounds of formula (I) whereby R1 and R3 are hydrogen and R2 and the C6(R4R5R6R7R8) moiety are identical, said compounds being represented by formula
(I-e), may be prepared by reacting an intermediate of formula (IX) wherein W2 is a suitable leaving group such as, for example, a halogen or the like, with an intermediate of formula (X) in a reaction inert solvent such as, for example, 1,4-dioxane. 
Compounds of formula (I) wherein R1 and R2 are other than hydrogen and are being represented by R1xe2x80x2 and R2xe2x80x2 respectively, said compounds being represented by formula (I-f-1), can be prepared by reacting an intermediate of formula (XI) with an intermediate of formula (XII) wherein W3 is a suitable leaving group such as, for example, a halogen, in a reaction-inert solvent such as, for example, N,N-dimethylformamide or N,N-dimethylacetamide, and in the presence of a suitable base such as, for example, sodium hydride or potassium carbonate. 
In case intermediate (XII) is limited to W3-Ar1 (XII-b) and R3 is hydrogen, the reaction time may be adjusted to form the disubstituted analogues being represented by formula (I-f-2). 
The compounds of formula (I) may further be prepared by converting compounds of formula (I) into each other according to art-known group transformation reactions.
For instance, compounds of formula (I-sa) may be reacted with an anhydride of formula (XIII) wherein R is defined such that xe2x80x94C(xe2x95x90O)xe2x80x94R is part of the definition of R1 or R2, according to the method described in Arch. Pharm. (Waldheim) 1986, 319, 275, thus forming compounds of formula (I-g). In this reaction, the reflux time is critical; longer times led to lower yield of the monosubstituted endproducts and increased formation of di- and where possible, trisubstituted endproducts. 
Compounds of formula (I-a) can also be reacted with a reagent of formula (XIV) in a reaction-inert solvent such as, for example, N,N-dimethylformamide, in the presence of a base such as, for example, sodium hydride. 
Some of the intermediates as mentioned hereinabove are commercially available or can be prepared according to art-known procedures, while other intermediates are deemed novel.
Intermediates of formula (II) can be prepared by reacting a cyano derivative of formula (XV) with ammonium chloride (XVI) or a functional derivative thereof in a reaction-inert solvent such as, for example, toluene, and in the presence of a suitable catalyst such as, for example, trimethylaluminium. 
Intermediates of formula (III) can generally be made by reacting diphenyl N-cyano-carbonimidate of formula (XVII), which can be prepared according to Webb R.L. et al., J. Heterocyclic Chem., 19:1205-1206 (1982), with an aniline derivative of formula (XVIII) in a reaction-inert solvent such as, e.g. N,N-dimethylformamide. 
Intermediates of formula (VII) can be prepared by first making a Grignard reagent of an intermediate of formula (XIX) wherein W4 is a suitable leaving group such as, for example, a halogen, e.g. bromine, in the presence of magnesium in a reaction-inert solvent such as, for example, diethyl ether, and subsequently reacting said Grignard reagent with an intermediate of formula (XX) wherein W5 is a suitable leaving group such as, for example, a halogen, e.g. chlorine, in a reaction-inert solvent such as, for example, benzene, thus forming an intermediate of formula (XXI). It may be convenient to perform the above reaction under a inert atmosphere such as, for instance, argon. Intermediate (XXI) may be isolated from its reaction medium, or may be in situ further reacted with an intermediate of formula (XXII) in a reaction-inert solvent such as, for example, 1,4-dioxane, and in the presence of a suitable base such as, for example, diisopropylethaneamine or the like, thus forming an intermediate of formula (VII). The intermediates of formula (VII) are deemed novel. 
Intermediates of formula (XI) can be prepared by reacting an intermediate of formula (XXIII) with an intewrmediate of formula (XXIV) in a reaction-inert solvent such as, for example, N,N-dimethylformamide. 
Compounds of formula (I) and some of the intermediates may have one or more stereogenic centers in their structure, present in a R or a S configuration.
The compounds of formula (I) as prepared in the hereinabove described processes may be synthesized as a mixture of stereoisomeric forms, in particular in the form of racemic mixtures of enantiomers which can be separated from one another following art-known resolution procedures. The racemic compounds of formula (I) may be converted into the corresponding diastereomeric salt forms by reaction with a suitable chiral acid. Said diastereomeric salt forms are subsequently separated, for example, by selective or fractional crystallization and the enantiomers are liberated therefrom by alkali. An alternative manner of separating the enantiomeric forms of the compounds of formula (I) involves liquid chromatography using a chiral stationary phase. Said pure stereochemically isomeric forms may also be derived from the corresponding pure stereochemically isomeric forms of the appropriate starting materials, provided that the reaction occurs stereospecifically. Preferably if a specific stereoisomer is desired, said compound will be synthesized by stereospecific methods of preparation. These methods will advantageously employ enantiomerically pure starting materials.
The compounds of formula (I) show antiretroviral properties, in particular against Human Immunodeficiency Virus (HIV), which is the aetiological agent of Acquired Immune Deficiency Syndrome (AIDS) in humans. The HIV virus preferentially infects human T-4 cells and destroys them or changes their normal function, particularly the coordination of the immune system. As a result, an infected patient has an everdecreasing number of T-4 cells, which moreover behave abnormally. Hence, the immunological defense system is unable to combat infections and neoplasms and the HIV infected subject usually dies by opportunistic infections such as pneumonia, or by cancers. Other conditions associated with HIV infection include thrombocytopaenia,
Kaposi""s sarcoma and infection of the central nervous system characterized by progressive demyelination, resulting in dementia and symptoms such as, progressive dysarthria, ataxia and disorientation. HIV infection further has also been associated with peripheral neuropathy, progressive generalized lymphadenopathy (PGL) and AIDS-related complex (ARC).
The present compounds also show activity against HIV-1 strains that have acquired resistance to art-known non-nucleoside reverse transcriptase inhibitors. They also have little or no binding affinity to human xcex1-1acid glycoprotein.
Due to their antiretroviral properties, particularly their anti-HIV properties, especially their anti-HIV-1-activity, the compounds of formula (I), their pharmaceutically acceptable salts and the stereochemically isomeric forms thereof, are useful in the treatment of individuals infected by HIV and for the prophylaxis of these individuals. In general, the compounds of the present invention may be useful in the treatment of warm-blooded animals infected with viruses whose existence is mediated by, or depends upon, the enzyme reverse transcriptase. Conditions which may be prevented or treated with the compounds of the present invention, especially conditions associated with HIV and other pathogenic retroviruses, include AIDS, AIDS-related complex (ARC), progressive generalized lymphadenopathy (PGL), as well as chronic CNS diseases caused by retroviruses, such as, for example HIV mediated dementia and multiple sclerosis.
The compounds of the present invention therefore may be used as medicines against above-mentioned conditions. Said use as a medicine or method of treatment comprises the systemic administration to HIV-infected subjects of an amount effective to combat the conditions associated with HIV and other pathogenic retroviruses, especially HIV-1.
The subject compounds may be formulated into various pharmaceutical forms for administration purposes. Said pharmaceutical forms or compositions are deemed novel and consequently constitute another aspect of the present invention. Also the preparation of said compositions constitutes a further aspect of the present invention. As appropriate compositions there may be cited all compositions usually employed for systemically administering drugs. To prepare the pharmaceutical compositions of this invention, an effective amount of the particular compound, optionally in acid addition salt form, as the active ingredient is combined in intimate admixture with a pharma- ceutically acceptable carrier, which carrier may take a wide variety of forms depending on the form of preparation desired for administration. These pharmaceutical compositions are desirable in unitary dosage form suitable, particularly, for administration orally, rectally, percutaneously, or by parenteral injection. For example, in preparing the compositions in oral dosage form, any of the usual pharmaceutical media may be employed such as, for example, water, glycols, oils, alcohols and the like in the case of oral liquid preparations such as suspensions, syrups, elixirs and solutions; or solid carriers such as starches, sugars, kaolin, lubricants, binders, disintegrating agents and the like in the case of powders, pills, capsules, and tablets. Because of their ease in administration, tablets and capsules represent the most advantageous oral dosage unit forms, in which case solid pharmaceutical carriers are obviously employed. For parenteral compositions, the carrier will usually comprise sterile water, at least in large part, though other ingredients, for example, to aid solubility, may be included. Injectable solutions, for example, may be prepared in which the carrier comprises saline solution, glucose solution or a mixture of saline and glucose solution. Injectable suspensions may also be prepared in which case appropriate liquid carriers, suspending agents and the like may be employed. Also included are solid form preparations which are intended to be converted, shortly before use, to liquid form preparations. In the compositions suitable for percutaneous administration, the carrier optionally comprises a penetration enhancing agent and/or a suitable wetting agent, optionally combined with suitable additives of any nature in minor proportions, which additives do not introduce a significant deleterious effect on the skin.
It is especially advantageous to formulate the aforementioned pharmaceutical compositions in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form as used herein refers to physically discrete units suitable as unitary dosages, each unit containing a predetermined quantity of active ingredient calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. Examples of such dosage unit forms are tablets (including scored or coated tablets), capsules, pills, powder packets, wafers, injectable solutions or suspensions and the like, and segregated multiples thereof.
Those of skill in the treatment of HIV-infection could determine the effective daily amount from the test results presented here. In general it is contemplated that an effective daily amount would be from 0.01 mg/kg to 50 mg/kg body weight, more preferably from 0.1 mg/kg to 10 mg/kg body weight. It may be appropriate to administer the required dose as two, three, four or more sub-doses at appropriate intervals throughout the day. Said sub-doses may be formulated as unit dosage forms, for example, containing 1 to 1000 mg, and in particular 5 to 200 mg of active ingredient per unit dosage form.
The exact dosage and frequency of administration depends on the particular compound of formula (I) used, the particular condition being treated, the severity of the condition being treated, the age, weight and general physical condition of the particular patient as well as other medication the individual may be taking, as is well known to those skilled in the art. Furthermore, it is evident that said effective daily amount may be lowered or increased depending on the response of the treated subject and/or depending on the evaluation of the physician prescribing the compounds of the instant invention. The effective daily amount ranges mentioned hereinabove are therefore only guidelines and are not intended to limit the scope or use of the invention to any extent.
Also, the combination of an antiretroviral compound and a compound of formula (I) can be used as a medicine. Thus, the present invention also relates to a product containing (a) a compound of formula (I), and (b) another antiretroviral compound, as a combined preparation for simultaneous, separate or sequential use in anti-HIV treatment. The different drugs may be combined in a single preparation together with pharmaceutically acceptable carriers. Said other antiretroviral compounds may be known antiretroviral compounds such as nucleoside reverse transcriptase inhibitors, e.g. zidovudine (3xe2x80x2-azido-3xe2x80x2-deoxythymidine, AZT), didanosine (dideoxy inosine; ddI), zalcitabine (dideoxycytidine, ddC) or lamivudine (3xe2x80x2-thia-2xe2x80x2-3xe2x80x2-dideoxycytidine, 3TC) and the like; non-nucleoside reverse transciptase inhibitors such as suramine, pentamidine, thymopentin, castanospermine, dextran (dextran sulfate), foscarnet-sodium (trisodium phosphono formate), nevirapine (11-cyclopropyl-5,1-dihydro-4-methyl-6H-dipyrido[3,2-b:2xe2x80x2,3xe2x80x2-e][1,4]diazepin-6-one), tacrine (tetrahydroaminoacridine) and the like; compounds of the TIBO (tetrahydro-imidazo[4,5,1-jk][1,4]-benzodiazepine-2(1H)-one and thione)-type e.g. (S)-8-chloro-4,5,6,7-tetrahydro-5-methyl-6-(3-methyl-2-butenyl)imidazo-[4,5,1-jk][1,4]benzodiazepine-2(1H)-thione; compounds of the xcex1-APA ((xcex1-anilino phenyl acetamide) type e.g. xcex1-[(2-nitro-phenyl)amino]-2,6-dichlorobenzene-acetamide and the like; TAT-inhibitors, e.g. RO-5-3335 and the like; protease inhibitors e.g. indinavir, ritanovir, saquinovir and the like; or immunomodulating agents, e.g. levamisole and the like.